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Inducing Tolerance to a Myelin Protein Reverses MS Symptoms in a Mouse Model.

Will the Gene Therapy Translate to Human Trials?

Robinson, Richard

doi: 10.1097/01.NT.0000552945.84962.a9
At the Bench
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ARTICLE IN BRIEF:

Figure

Figure

In a gene therapy study, the expression of myelin oligodendrocyte glycoprotein had an immunomodulatory effect, leading to a reversal of paralysis in an animal model of multiple sclerosis.

Reducing autoimmunity through tolerizing T cells to self-antigens has been a long sought goal in development of multiple sclerosis (MS) therapy. Now a study shows that in a mouse model of MS, gene therapy that prompts expression of one such antigen, myelin oligodendrocyte glycoprotein (MOG), in the liver increases the level of regulatory T cells and reverses clinical symptoms of the disease.

But while experts praised the results, at least one MS researcher said he doubts the technique will ultimately be clinically useful for MS patients.

“We've known for a long time that antigens put into the liver tend to induce tolerance,” commented David A. Hafler, MD, FANA, of Yale University, who was not involved in the study. “The authors have very convincingly shown that by doing so with an MOG antigen, they had an effect on experimental autoimmune encephalitis [EAE]. But in MS there isn't just one antigen. There are many.”

“T cell activation occurs along one of two pathways,” explained the lead investigator on the new study, Brad E. Hoffman, PhD, professor of pediatrics and neuroscience at the University of Florida College of Medicine in Gainesville. “It can become an activated effector cell that targets an antigen, or it can become a regulatory cell, counterbalancing the effector cells and preventing their overreaction.”

MOG is a protein on the outer coat of the myelin that wraps axons, and is a target for attack by effector T cells in MS. One widely studied strategy for MS therapy is to increase the proportion of regulatory T cells (Tregs) to keep the effectors in check.

One approach to that end has been ex vivo proliferation and then reinfusion of Tregs, but the cells don't last long, Dr. Hoffman said. The alternative is stimulating Treg proliferation within the body itself, by exposing resident T cells to the appropriate antigen in a tolerogenic environment such as the liver.

“By providing the antigen to the liver, we can continuously promote production of the regulator T cells in vivo, allowing them to maintain protection over a long period of time,” Dr. Hoffman said.

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Study Design

For the current study, Dr. Hoffman used an adeno-associated virus (AAV) containing the gene for the full-length MOG protein with a liver-specific promoter. Taken up by hepatocytes, expression of the gene led to a sharp increase in the number of MOG-specific Tregs, and to suppression of MOG-specific effector cells, he and his colleagues reported early in 2018 in Molecular Therapy.

To determine if pretreatment could prevent development of EAE, Dr. Hoffman injected mice with either AAV/MOG or a control vector, and two weeks later induced EAE by injection of a fragment of the MOG protein. Control-injected mice developed clinical signs of disease within 10 days, while those injected with AAV/MOG remained unaffected through the end of the experiment at 30 days.

In a second experiment designed to evaluate long-term robustness, Dr. Hoffman waited approximately 200 days to induce EAE, and found similar results: Control-treated animals developed EAE within two weeks, while AAV/MOG treated animals remained healthy.

“Even after more than half a year, the treatment is still protective,” he said.

Of potentially more clinical significance, Dr. Hoffman tested the effect of treatment after onset of disease. After induction of EAE, mice reaching a predetermined clinical score were injected with either active treatment or control. Both groups of mice developed severe paralysis, but those treated with AAV/MOG then had a reversal of course.

When treated at the earliest stages of the disease, mice recovered almost completely. Later treatment resulted in less dramatic but still significant improvement. That improvement could be enhanced, the team found, by administering rapamycin immediately after AAV/MOG. While rapamycin provided only temporary benefit to control-treated mice, it synergistically led to complete and sustained remission in those receiving AAV/MOG, even if treatment began after they were severely affected.

“Rapamycin reduces the active inflammatory activity of effector cells, preventing them from proliferating,” Dr. Hoffman said. This in effect provides Tregs a foothold as they begin influencing effector cell activity.

Should this therapeutic approach be translated to humans, “the goal would be to ‘reeducate’ the immune system” to reduce the response to MOG, Dr. Hoffman said, “instead of giving a lifetime of immune-suppressive drugs.”

The translational benefits such an approach might provide in MS are difficult to predict, but are likely to be largest in early MS, he added. “The EAE mouse mimics the earliest stages of MS, not the neurodegenerative phase. ‘Very late’ for the mouse disease is still very early in human terms.”

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Expert Commentary

“The findings in this study are quite exciting,” commented Bellur S. Prabhakar, PhD, professor and head of the department of microbiology and immunology at the University of Illinois in Chicago. While the results are correlative, in that they have not proven the protective effect was due solely to the increase in MOG-specific Tregs, “they are very encouraging,” he said.

The question of MOG's relevance to human MS remains, but may not be crucial if this strategy provides a way to greatly increased Tregs. “As long as they are in a milieu where pathogenic T cells exist,” Dr. Prabhakar said, “they are going to exert their suppressive function, irrespective of the antigen specificity. Increasing regulatory T cells should be good for the patient.”

Dr. Hafler, Yale professor of neurology and immunobiology, and neurologist-in-chief at Yale New Haven Hospital, is more circumspect about the translational potential of MOG-specific tolerization.

“The study is very well-done, and the data are quite convincing, but the fundamental question is what the role of MOG is in human MS,” he said.

“The EAE model is an excellent model for studying events after induction of inflammatory T cells and their passage into the brain,” Dr. Hafler said, noting that this aspect of the model predicted the efficacy of drugs such as natalizumab (tysabri) that block that passage. “But it is less useful for understanding the induction of reactive T cells.”

Not only are there other proteins that can induce EAE (and presumably MS), he said, “but whatever the inciting antigen is, we know that within weeks there is epitope spreading,” in which the immune system begins to react to multiple other epitopes of both the same and other proteins. Thus protection against a single antigen is unlikely to provide protection in the complex and dynamic environment of developing MS, he said, a situation further complicated by the wide variety of genetic contributors to MS susceptibility, which are likely to influence treatment response as well.

“We currently have therapies that can essentially shut down the disease,” Dr. Hafler said. “Because of that, it's not clear that a virally delivered gene for a self-antigen to induce tolerance is likely to find clinical utility.”

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Disclosures

Drs. Hoffman and Prabhakar had no conflicts.

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Link Up for More Information

•. Keeler GD, Kumar S, Palaschak B, et al Gene therapy-induced antigen-specific Tregs inhibit neuro-inflammation and reverse disease in a mouse model of multiple sclerosis https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(17)30413-6. Mol Ther 2018;26(1):173–183.
    © 2019 American Academy of Neurology